Alzheimer?s disease (AD) is a progressive neurodegenerative disease with clinical features that include memory loss, cognitive impairment and dementia. According to 2017 data from the Alzheimer?s Association, AD is the 6th leading cause of death in the U.S. and will cost the nation $259 billion dollars this year. More than 5 million Americans currently live with the diagnosis of AD and it is expected to increase to as much as 16 million by 2050. Current treatments for AD have very limited efficacy and thus there is a significant need for improved pharmacological therapies. AD is characterized by the formation of senile plaques and neurofibrillary tangles in the grey matter of affected individuals. The senile plaques are composed of extracellular deposition of insoluble amyloid beta (A?) peptides that are typically associated with a wealth of microglia (brain resident macrophages) and astrocytes. It is generally recognized that the extracellular accumulation of A? is a key event the pathogenesis of AD. Inflammation induced by accumulation of A? is believed to be a crucial factor underlying the neural dysfunction and microglia and bone marrow derived phagocytes recruited to the plaques are fundamental to the pathogenesis of AD. We discovered that the REV-ERB nuclear receptors play a critical role in regulation of neuroinflammation and that pharmacological activation of REV-ERB effectively reduces neuroinflammation and improves cognitive function in a model of AD. The goal of this project is to develop optimized REV-ERB agonists that may be effective agents for reduction of neuroinflammation in treatment of Alzheimer?s disease and, potentially, other neurodegenerative disorders associated with neuroinflammation.